Vitamin



Patented June 17, 1947 UNITED STATES PATENT OFFICE VITAMIN Be INTERMEDIATES AND PROCESS OF PREPARING THE SAME Stanton A. Harris, Westfield, N. J assignor to Merck & 00., Inc., Rahway, N. J a corporation of New Jersey No Drawing. Application July 22, 1943, Serial No. 495,772

12 Claims. (Cl. 260-297) GHaOR I! CN CHnOR wherein R is an alkyl, an arylalkyl, or an aryl group, can be indicated as follows:

CHz-OR CHzOR HzG -CN ON on, o {I I I HICC HaC N OH wherein X is or =NI-I and Y is -CN, COOR or CONH2.

The above reaction product can exist in the indicated enol-form or in its keto-form equilibrant:

CHzOR It is remarkable that the above condensation re:-

action proceeds to form the indicated product in large yield without formation of the alternative condensate:

ROCH on The reaction can occur in aqueous or alcoholic solvents and is preferably performed in the presence of ammonia or a secondary amine. The ammonia, if desired, can be reacted with the di ketone or cyanoacetic ester prior to or concurrently with the condensation reaction. The condensation reaction is favorably catalyzed by secondary amines such as saturated aliphatic amines (dimethylamine, diethylamine, and their homologs) unsaturated aliphatic amines (diallylamine, dicrotylamine, and their homologs), aliphaticaromatic amines (methylbenzylamine and its homologs), and N-heterocyclic compounds having secondary amine characteristics, particularly piperidine. Inasmuch as the secondary amine serves merely as a catalyst in the condensation reaction, it will be obvious that the relative quantity present in the reaction mixture above the minimum required for optimum speed of reaction,

is not critical.

The following examples illustrate methods of carryingout the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

Emample 1 Approximately 1.2 mols (about g.) of cyanoacetamide (HzN.CO.CI-I2.CN) are dissolved in about 750 cc. of hot ethanol (95%) and approximately 1 mol (about g.) of methoxyacetylacetone (H3C.CO.CH2.CO.CI-12OCH3) and 10 cc. of piperidine are added with agitation of the mixture. The ensuing reaction is somewhat exothermic, accordingly the mixture is cooled. After standing, cooling, filtering and washing the crystals thus obtained with ethanol, the product, 3--cyano-4methoxymethyl-6 methyl-pyridone-2, is obtained and, if desired can be further purified by crystallization from alcohol. M. P. about 240 C. corr. If desired, an equivalent quantity of a different secondary amine can be substituted for the piperidine, for example, one of the amines mentioned above in the general description of this invention.

Example 2 To about 65 .3 g. of cyanoaoetamide (H2N.CO.CH2.CN)

amines can be substituted for piperidine as a 7 catalyst for the reaction.

Example 3 About 50 g. (.6 mol.) of cyanoacetamide (H2N.CO.CH2.CN) are dissolved in approximately 350 cc. of hot ethanol (95%) and about 79g. (.5 mol.) of propoxyacetylacetone and about 5 cc. of piperidine are added, the mixture being cooled and agitated during the addition. After standing, cooling, filtering, and washing as in the foregoing examples, the product is obtained, 3-cyano-4-propoxymethyl-6-methylpyridone-2.

Example 4 About 1 g. of cyanoacetamide (H2N.CO. CI-Iz.CN)

are dissolved in approximately '750 cc. of hot ethanol (95%) and about 192 g. of phenoxyacetylacetone (HaC.CO.CI-I2.CO.CI-I2OCsI-I5) and 10 cc. of piperidine are added with agitation'to the mixture which is thereafter further processed as in Example 1. The product obtained is 3-cyano- 4-phenoxymethyl-G-methyl-pyridone-2.

Example 5 About 84 gms. of cyanoacetamide are dissolved in approximately 740 cc. of hot ethyl alcohol and to this solution 130 gms. of methoxyacetylacetone are added. When the temperature of the solution has dropped to 60 0., 12 cc. of piperidine are added slowly with stirring. The color of the solution turns dark red and the temperature rapidly rises to 70 C. Crystals soonappear and the temperature rises to 78 C. The alcohol boils for about one half hour and the mixture becomes a thick mass of crystals. The mixture is allowed to stand over night at room temperature. After filtering and washing with ethanol and ether, the precipitate of 3-cyano-4-methoxymethyl-6- methy1pyridone-2 is separated and recrystallized from glacial acetic acid (M. P., 242243 C.)

Example 6 About 1.13 gms. of ethyl cyanoacetate are dissolved in approximately 5 cc. of cold concentrated ammonia water and about 1.44 gms. of l-methoxy-2,4-hexadiene are added. After a few minutes, 3-cyano-4-methoxymethyl 6 ethyl-pyridone-2 separates as a White crystalline solid, M. P. 187 C. The mixture is diluted with water, filtered and. the residue washed with water, alcohol and ether. 7

In like manner, other alkoxyacetylacetones, aryloxyacetylacetone, and arylalkoxyacetylacetones can be condensed with cyanoacetamide to producethe corresponding 4-alkoxymethyl, 4- aryloxymethyl, or 4-arylalkoxyacetylacetones.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof and the invention is to be limited only by the appended claims.

4 What is claimed is: 1. Compounds represented by the formula;

OHzOR 5 ma H3CN OH wherein R. is an alkyl group.

10 2. Compounds represented by the formula:

CHzOR Ha CLN wherein R is an aryl group.

3. The compound represented by the formula:

CHzOCzHa H3O OH 4. The compound represented by the formula:

OHgOCzH7 E OH 5. The compound represented by the formula:

O H30 OH N 6. The process that comprises reacting a 1-alkoxy-2z4 diketo pentane with cyanoacetamide as. represented by the following reaction:

CHzO R E CHZO R HzO-CN CH1 0 I in presence of 8 ON I (3:0 H3O C H N/ secondary amine H O OH a o 2 N wherein R is an alkyl group.

7. The process that comprises reacting a 1- aryloxy 2:4-diketo pentane with cyanoacetamide as represented by the following reaction:

CHROR CHzOR H; In presence of a wherein R is an aryl group.

8. The process that comprises reacting 1- ethoxy-Z:4-diketo-pentane with cyanoacetamide as represented by the. following reaction:

9. The process that comprises reactingl-butyl- 2,422,616 5 6 oxy-2z4- diketo-pentane with cyanoacetamide 12. The process that comprises reacting cyas represented by the following reaction: anoacetamide with a substance selected from the class consisting of 1-alkoxy-2:4 diketo penonto C3117 l H 0 C H tanes and l-aryloxy 2:4-diketo pentanes as H2C CN a 1 5 represented by the following reaction: OH; O l in presence of a V GN CH OR H 023 /O:0 secondary amine I a HQN H30 OH H2C CN onion 1 0 1511 t I: 1 ([JH: O O in presence ofa ON 0. The process a comprises reac ing phenoxy-ZA diketo pentane with cyanoacetk H N secondary amme H3O OH amide as represented by the following reaction: 0 N

cmo 06115 wherein R is a radical selected from the class con- 0 0132005115 sisting of alkyl and aryl groups. 0% \O H2(|J ON in resence ofa ON I l a 6:0 I STANTON A. HARRIS. H30 0 secondary amine \O HQN H3O N H REFERENCES CITED 1L ccmpounds represented by the formula; The following references are of record in the CHZOR 0 file of this patent:

0N UNITED STATES PATENTS l Number Name Date H3O O 2,248,078 Harris July 8, 1941 OTHER REFERENCES wherein R is a radical selected from the class 0011- Enzymologia, VII, 28 291, 1939, pp. 3856,

sisting of alkyl and aryl groups. 

